ARL-17477 is a dual inhibitor of NOS1 and the autophagic-lysosomal system that prevents tumor growth in vitro and in vivo

  • Sci Rep. 2023 Jul 4;13(1):10757. doi: 10.1038/s41598-023-37797-4.
Teiko Komori Nomura  1 ,  Satoshi Endo  2  3 ,  Takuma Kuwano  4 ,  Kazuya Fukasawa  5 ,  Shigeo Takashima  1  3  6  7 ,  Tomoki Todo  8 ,  Kyoji Furuta  1  9 ,  Takuhei Yamamoto  1  3  4 ,  Eiichi Hinoi  1  3  5 ,  Hiroko Koyama  1  9 ,  Ryo Honda  10  11
Affiliations
  • 1. United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
  • 2. Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
  • 3. Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan.
  • 4. Laboratory of Pharmaceutical Analytical Chemistry, Gifu Pharmaceutical University, Gifu, Japan.
  • 5. Laboratory of Pharmacology, Department of Bioactive Molecules, Gifu Pharmaceutical University, Gifu, Japan.
  • 6. Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan.
  • 7. Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan.
  • 8. Division of Innovative Cancer Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 9. Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan.
  • 10. United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan. [email protected].
  • 11. Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan. [email protected].
PMID: 37402770 DOI: 10.1038/s41598-023-37797-4
Abstract

ARL-17477 is a selective neuronal nitric oxide synthase (NOS1) inhibitor that has been used in many preclinical studies since its initial discovery in the 1990s. In the present study, we demonstrate that ARL-17477 exhibits a NOS1-independent pharmacological activity that involves inhibition of the autophagy-lysosomal system and prevents Cancer growth in vitro and in vivo. Initially, we screened a chemical compound library for potential Anticancer agents, and identified ARL-17477 with micromolar Anticancer activity against a wide spectrum of cancers, preferentially affecting Cancer stem-like cells and KRAS-mutant Cancer cells. Interestingly, ARL-17477 also affected NOS1-knockout cells, suggesting the existence of a NOS1-independent Anticancer mechanism. Analysis of cell signals and death markers revealed that LC3B-II, p62, and GABARAP-II protein levels were significantly increased by ARL-17477. Furthermore, ARL-17477 had a chemical structure similar to that of chloroquine, suggesting the inhibition of autophagic flux at the level of lysosomal fusion as an underlying Anticancer mechanism. Consistently, ARL-17477 induced lysosomal membrane permeabilization, impaired protein aggregate clearance, and activated transcription factor EB and lysosomal biogenesis. Furthermore, in vivo ARL-17477 inhibited the tumor growth of KRAS-mutant Cancer. Thus, ARL-17477 is a dual inhibitor of NOS1 and the autophagy-lysosomal system that could potentially be used as a Cancer therapeutic.

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